Title

Author

Date Submitted

Spring 4-17-2015

Restricted/Unrestricted

Dissertation/Thesis

Abstract

Genomic stability is vital for the survival of cells and organisms. Telomeres, the nucleoprotein complexes capping the ends of linear chromosomes, prevent loss of genetic information and play an important role in the regulation of cell division. Due to their repetitive sequence and ability to form secondary structures, telomeres are especially sensitive to mutations or deletions of DNA replication and repair proteins. Telomere fragility, a phenotype in which multiple telomere signals or aberrant signals are observed on metaphase chromosomes stained by fluorescent in situ hybridization, is induced when cells experience replication stress. Although telomere fragility has been observed in many different cell types, the phenotype remains poorly understood. It is unknown what the long-term consequences of fragile telomere expression are for a cell, as telomere fragility has not been monitored over an extended period following induction. In this work, we demonstrate that telomere fragility induced by aphidicolin treatment returns to control levels after two days and remains at this baseline for at least one week. Moreover, we find that the rate of cell death remains low (<0.2%) from induction through five days following aphidicolin treatment, demonstrating that it is unlikely that the decrease in telomere fragility is due to the elimination of cells with fragile telomeres. This result, along with our observation that telomere fragility induced upon aphidicolin treatment occurs in a majority of the cells in a population, allows us to conclude that cells have a mechanism to resolve telomere fragility. Since telomere fragility can be resolved within two cell cycles, additional factors, such as prolonged replication stress or greater damage, would likely be needed to create genomic instability and initiate tumorigenesis from breakage at fragile sites. Our findings contribute to a better understanding of telomere maintenance and repair that may play a prominent role in future work on telomere and cancer biology.